The splenon the functional unit of splenic RBC filtration. Blood flow is from top right to bottom left and may follow 2 parallel paths. The fast and closed circulation flows from splenic artery to central arterioles and their branches, then through the perifollicular zone (PFZ), PFZ-to-sinus by-passes, sinus lumens, postsinusal veinules that join into the splenic vein, and accounts for 80%-90% of the splenic blood flow. The slow open circulation has at least 2 specificities: (i) a microcirculatory structure devoid of endothelial cells where cord macrophages, and reticular cells survey the slowly migrating blood cells and (ii) narrow and short interendothelial slits in the sinus wall that RBC must cross to get back to the general circulation. The splenon displays analogies and differences with the nephron (see text). Schematically, the filtering function of the spleen can be divided in 3 successive steps. The “prefiltration step” (1) corresponds to the close contacts between RBCs and macrophages in the cords. RBC retention during this step is putatively triggered by ligand-receptor interactions, including direct recognition of RBC surface alterations and opsonization. The “filtration” step (2) corresponds to the crossing of interendothelial slits. RBC retention here is triggered by mechanical alterations. Undeformable bodies can also be extracted from RBCs in a process called pitting. The “postfiltration” step (3) corresponds to the modifications and processing of retained RBCs. Both the prefiltration and postfiltration steps potentially result in the phagocytosis of abnormal, decorated, or opsonized RBCs. Phagocytosis of parasitized RBCs is an initial step of antigen presentation to immune cells, thereby connecting filtration to the antigen-specific response.